| 1. |
- Diehl, Carl, et al.
(författare)
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Protein Flexibility and Conformational Entropy in Ligand Design Targeting the Carbohydrate Recognition Domain of Galectin-3.
- 2010
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 132, s. 14577-14589
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Tidskriftsartikel (refereegranskat)abstract
- Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy.
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| 2. |
- Verteramo, Maria Luisa, et al.
(författare)
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Interplay of halogen bonding and solvation in protein-ligand binding
- 2024
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Ingår i: iScience. - 2589-0042. ; 27:4
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Tidskriftsartikel (refereegranskat)abstract
- Halogen bonding is increasingly utilized in efforts to achieve high affinity and selectivity of molecules designed to bind proteins, making it paramount to understand the relationship between structure, dynamics, and thermodynamic driving forces. We present a detailed analysis addressing this problem using a series of protein-ligand complexes involving single halogen substitutions - F, Cl, Br, and I - and nearly identical structures. Isothermal titration calorimetry reveals an increasingly favorable binding enthalpy from F to I that correlates with the halogen size and σ-hole electropositive character, but is partially counteracted by unfavorable entropy, which is constant from F to Cl and Br, but worse for I. Consequently, the binding free energy is roughly equal for Cl, Br, and I. QM and solvation-free-energy calculations reflect an intricate balance between halogen bonding, hydrogen bonds, and solvation. These advances have the potential to aid future drug design initiatives involving halogenated compounds.
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| 3. |
- Falk, Magnus, et al.
(författare)
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Mechanism of Bilirubin Oxidase : Fabrication and Characterization of Efficient Biocathode
- 2010
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Ingår i: Meeting abstracts (Electrochemical Society). - : ECS. - 1091-8213 .- 2151-2043. ; MA2010-02:1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- To elucidate the mechanism of bilirubin oxidase (BOx)function in order to design efficient and stablebiocathodes working at different conditions, the enzymewas studied thoroughly. BOx is a copper-containing redoxenzyme that catalyzes the oxidation of a variety ofdifferent organic and inorganic compounds withconcomitant reduction of O2 directly to H2O.
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| 4. |
- Olsen, Lars, et al.
(författare)
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Prediction of activation energies for hydrogen abstraction by cytochrome P450
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 49:22, s. 6489-6499
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Tidskriftsartikel (refereegranskat)abstract
- We have estimated the activation energy for hydrogen abstraction by compound I in cytochrome P450 for a diverse set of 24 small organic substrates using state-of-the-art density functional theory (B3LYP). We then show that these results can be reproduced by computationally less demanding methods, for example, by using small organic mimics of compound I with both B3LYP and the semiempirical AM1 method (mean absolute error of 3-4 kJ/mol) or by calculating the bond dissociation energy, without relaxation of the radical (B3LYP) or estimated from three-point fit to a Morse potential (AM1; errors of 4 and 5 kJ/mol, respectively). We can assign activation energies of 74, 61, 53, 47, and 30 kJ/mol to primary carbons, secondary/tertiary carbons, carbons with adjacent sp(2) or aromatic groups, ethers/thioethers, and amines, respectively, which gives a very simple and predictive model. Finally, some of the less demanding methods are applied to study the CYP3A4 metabolism of progesterone and dextromethorphan.
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| 5. |
- Ryde, Ulf
(författare)
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A fundamental view of enthalpy-entropy compensation
- 2014
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2511. ; 5:9, s. 1324-1336
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, enthalpy-entropy compensation (EEC) during the association of two molecules is studied by minimising model systems with molecular mechanics (MM) or quantum mechanics (QM), calculating translational, rotational, and vibrational contributions to the enthalpy and entropy with standard statistical-mechanics methods, using the rigid-rotor harmonic-oscillator approach. We start with simple two-atom models, for which dispersion and electrostatics can be studied separately, showing that there is no fundamental difference between dispersion, electrostatics, or even covalent interactions. All three types of interactions give rise to EEC and a saturation of T Delta S as Delta H becomes strongly negative. Next, homologous series of complexes dominated either by dispersion or hydrogen bonds are studied. We see no qualitative difference between results obtained at the MM or QM level, and for all complexes except two very weak, EEC is observed, owing to the loss of translational and rotational entropy, typically counteracted by the vibrational entropy. Within homologous series, linear relations between T Delta S and Delta H with slopes of 0.1-1.7 are obtained with no clear difference between dispersive or hydrogen-bonded systems (but similar to 0.01 for ionic and covalent interactions). These relations often reflect the increasing size of the complexes coming from the translational and rotational entropies, but at least for the hydrogen-bonded complexes, it is significantly enhanced also by the vibrational entropy (which depends on the strength of the interaction). Thus, for homologous series of molecules with repeated interactions studied in vacuum, EEC is a rule. However, if water molecules are added, the relation is blurred and it can be predicted that for a real binding reaction in water solution, both enthalpy-entropy compensation and anti-compensation can be observed, depending on the detailed interaction of the two molecules with water before and after binding, further complicated by dynamic effects.
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| 6. |
- Söderhjelm, Pär, et al.
(författare)
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Quantum mechanics in structure-based ligand design
- 2012
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Ingår i: Protein-ligand interactions. - Weinheim, Germany : Wiley-VCH Verlag GmbH & Co. KGaA. - 9783527329663 - 9783527645947 ; 53, s. 121-143
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Bokkapitel (refereegranskat)
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| 7. |
- Weis, Aaron, et al.
(författare)
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Ligand affinities predicted with the MM/PBSA method: Dependence on the simulation method and the force field
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 49:22, s. 6596-6606
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Tidskriftsartikel (refereegranskat)abstract
- The free energy of binding between avidin and seven biotin analogues has been calculated with the molecular mechanics Poisson- Boltzmann surface area (MM/PBSA) method. We have studied how the force field and the method to generate geometries affect the calculated binding free energies. Four different force fields were compared, but we saw no significant difference in the results. However, mixing the force fields used for the geometry generation and energy calculations is not recommended. In the molecular dynamics simulations, explicit water molecules must be used, but the size of the simulated system and the boundary conditions are less important. In fact, nonperiodic simulations with a fixed protein outside a relatively small simulated system (18 angstrom) seem to be a proper approach. The mean absolute error was 9-19 kJ/mol, with a standard error of 5-15 kJ/mol, which arises mainly from the entropy term.
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